tbuckley/cabot-search huggingface dataset:
Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper
Authors: Giuditta Illuzzi, Anna D. Staniszewska, Sonja J. Gill, Andy Pike, Lisa McWilliams, Susan E. Critchlow, Anna Cronin, Stephen Fawell, Glen Hawthorne, Kunzah Jamal, Jeffrey Johannes, Emilyanne Leonard, Ruth Macdonald, Gareth Maglennon, Jenni Nikkilä, Mark J. O'Connor, Aaron Smith, Harriet Southgate, Joanne Wilson, James Yates, Sabina Cosulich, Elisabetta Leo
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination. Experimental Design: AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination. Results: AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response. Conclusions: AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
Complete closure of mucosal defect after colonic endoscopic submucosal dissection using clip with a silicone traction band
Authors: Kosuke Maehara, Mitsuru Esaki, Yorinobu Sumida, Shin-ichro Fukuda, Yosuke Minoda, Eikichi Ihara, Hirotada Akiho
Journal: Endoscopy (2022)

Endoscopic submucosal dissection (ESD) is a standard treatment for colorectal neoplasms, but the risk of severe postoperative complications persists even after successful ESD [1] [2]. Therefore, complete closure of defects after ESD is essential to prevent such complications [3]. Although complete closure is a technically difficult procedure, several techniques have been developed to assist [4] [5]. Herein, we present a case of successful complete closure of a mucosal defect after colonic ESD using clips with a silicone traction band ([Fig. 1]).
Endoscopic ultrasound-guided through-the-needle biopsy for the diagnosis of cystic tumors of the pancreas: not for all patients
Authors: Enrique Vázquez-Sequeiros
Journal: Endoscopy (2022)

The increasing incidence of pancreatic cystic lesions (PCLs) represents a major problem in Western countries [1] [2]. First of all, we have to accurately establish in a minimally invasive fashion the diagnosis of the nature of the cyst. Noninvasive imaging techniques like computed tomography scanning or magnetic resonance imaging are not able to differentiate the type of tumor in a significant proportion of patients [2]. Furthermore, establishing a diagnosis of malignant or benign disease may be impossible in the early stages. Unfortunately, endoscopic ultrasound (EUS) image criteria, as well as EUS-guided fine-needle aspiration (EUS-FNA) of the cyst content for analysis, have been revealed to be suboptimal [2]. Most samples obtained from PCLs are poorly cellular and, despite advances in tumor markers (glucose, amylase, carcinoembryonic antigen [CEA], K-Ras, G-NAS, among others), fluid analysis is not able to provide a definitive diagnosis in a significant proportion of patients [2]. In recent years, some improvements to solve this problem have been introduced, such as EUS-guided laser confocal endomicroscopy for the characterization of the cyst wall, with promising results for the differentiation of serous and mucinous type PCLs [3]. However, the high cost of this type of device is likely to preclude its widespread use in clinical practice in the coming years.
An unusual malignant main bile duct stricture: a biliary metastasis of endometrial adenocarcinoma.
Authors: Pierre Mayer, Lucile Héroin, Gerlinde Averous, Mathieu Pioche, Gabriel Lepeut, Emanuele Felli, François Habersetzer
Journal: Endoscopy (2022)

Biliary strictures are frequently encountered in interventional endoscopy. Their etiological diagnosis may be complicated [1]. Endoscopic ultrasound (EUS) guided biopsies, brush cytology, and wire-guided biopsies allow a diagnosis in most cases. Single-operator cholangioscopy (SOC) has radically changed the diagnostic approach, allowing visualization of the lesion, endoscopic characterization, and targeted biopsies [2].
Safe removal of a synthetic paper for cake decoration that had caused a hemorrhagic rectal ulcer using a detachable snare after hemostatic treatment
Authors: Yasuhiko Nakao, Fumihiro Mawatari, Tetsuhiko Arima, Sachiko Fukuda, Yoshiko Kita, Aiko Fukahori, Kazuhiko Nakao
Journal: Endoscopy (2022)

An 80-year-old woman, who had just eaten a shortcake, realized that she had accidentally eaten the cake's decorative paper. She did not initially experience any symptoms but, 2 months later, she was unable to eat and became bedridden. A short time later, she was admitted to the neurosurgery department of our hospital with impaired consciousness. She was diagnosed with extensive cerebral embolism and was treated conservatively. Her level of consciousness improved and she was started on tube feeding. A few days later, she passed a large amount of melena and was referred to the gastroenterology department.
Massive bleeding on removing a stent placed during endoscopic ultrasound-guided transluminal drainage
Authors: Ikuhisa Takimoto, Tomoaki Matsumori, Masataka Yokode, Masahiro Shiokawa, Norimitsu Uza, Hiroshi Seno
Journal: Endoscopy (2022)

A 67-year-old man with pancreatic head cancer developed acute pancreatitis due to obstruction of the main pancreatic duct. He subsequently developed an infected walled-off necrosis (WON) ([Fig. 1]). Endoscopic ultrasound-guided transluminal drainage (EUS-TD) was performed using a 6-Fr endoscopic nasobiliary drainage catheter (SilkyPass; Boston Scientific, Tokyo, Japan) as an external drainage tube and a 7-Fr/7-cm double-pigtail plastic stent (DPS) (Zimmon biliary stent; Cook Medical, Tokyo, Japan) as an internal drainage tube ([Fig. 2]). Subsequently, the patient's condition improved, and the external drainage tube was removed. Computed tomography (CT) performed 4 months after EUS-TD revealed that the WON had disappeared. The DPS was in place until pancreaticoduodenectomy after neoadjuvant chemotherapy and was removed endoscopically 8 months after EUS-TD because of the risk that the DPS could cause infection during adjuvant chemotherapy. At the time the stent was removed, massive arterial bleeding occurred from the fistula ([Video 1]). Since endoscopic hemostasis was difficult, urgent interventional radiology was performed, and a splenic artery pseudoaneurysm causing massive bleeding was detected ([Fig. 3]). Hemostasis was achieved using coil embolization ([Fig. 4]).
The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty
Authors: Vinicius N Brito, Ana P M Canton, Carlos Eduardo Seraphim, Ana Paula Abreu, Delanie B Macedo, Berenice B Mendonca, Ursula B Kaiser, Jesús Argente, Ana Claudia Latronico
Journal: Endocrine Reviews (2022)

The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Endoscopic submucosal dissection for a superficial esophageal squamous cell carcinoma located in a Rokitansky diverticulum
Authors: Kosuke Tanaka, Yohei Yabuuchi, Daisuke Yamashita, Kazuya Hosotani, Shuko Morita, Tetsuro Inokuma
Journal: Endoscopy (2022)

Lesions in the esophageal diverticulum are at risk of perforation during endoscopic resection due to a lack of or thinned muscularis propria [1]. We successfully performed endoscopic submucosal dissection (ESD) for superficial esophageal cancer in a Rokitansky diverticulum.
Through-the-scope suture closure of peroral endoscopic myotomy mucosal incision sites
Authors: Linda Yun Zhang, Michael Bejjani, Bachir Ghandour, Mouen A. Khashab
Journal: Endoscopy (2022)

Abstract Background Peroral endoscopic myotomy (POEM) is now widely used for esophageal motility disorders including achalasia. Closure of the mucosal incision site is a critical step of the procedure. We evaluated the use of a novel through-the-scope (TTS) suture system for closure of POEM mucosal incision sites. Methods We retrospectively reviewed consecutive patients who underwent POEM with TTS suture closure at our institution between February and July 2021. Technical success was defined as complete mucosal incision site closure using TTS suturing, without the need for adjunctive devices. Continuous variables are presented as median (interquartile range [IQR]) or mean (SD). Results 35 consecutive patients (median age 58 years [IQR 46.5–72]; 54.3 % female) underwent POEM with attempted mucosal closure by TTS suturing. Technical success was achieved in 32 patients (91.4 %) with a mean closure time of 12.4 (SD 6.9) minutes. The median mucosal incision length at time of closure was 2.5 cm (IQR 2–2.5). Overall, 17 patients (53.1 %) required ≥ 2 TTS suture systems and 3 patients (8.6 %) required additional TTS clips to achieve secure mucosal closure. No adverse events were encountered. Conclusions TTS suturing was effective and safe for POEM mucosotomy closure. However, prospective comparative trials and cost-effectiveness analyses are warranted before routine adoption.
Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies
Authors: Yuangang Wu, Jiao Li, Yi Zeng, Wenchen Pu, Xiaoyu Mu, Kaibo Sun, Yong Peng, Bin Shen
Journal: International Journal of Oral Science (2022)

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management.
One‐Step Bioprinting of Multi‐Channel Hydrogel Filaments Using Chaotic Advection: Fabrication of Pre‐Vascularized Muscle‐Like Tissues
Authors: Edna Johana Bolívar‐Monsalve, Carlos Fernando Ceballos‐González, Carolina Chávez‐Madero, Brenda Guadalupe de la Cruz‐Rivas, Silvana Velásquez Marín, Shirley Mora‐Godínez, Luisa María Reyes‐Cortés, Ali Khademhosseini, Paul S. Weiss, Mohamadmahdi Samandari, Ali Tamayol, Mario Moisés Alvarez, Grissel Trujillo‐de Santiago
Journal: Advanced Healthcare Materials (2022)

Abstract The biofabrication of living constructs containing hollow channels is critical for manufacturing thick tissues. However, current technologies are limited in their effectiveness in the fabrication of channels with diameters smaller than hundreds of micrometers. It is demonstrated that the co‐extrusion of cell‐laden hydrogels and sacrificial materials through printheads containing Kenics static mixing elements enables the continuous and one‐step fabrication of thin hydrogel filaments (1 mm in diameter) containing dozens of hollow microchannels with widths as small as a single cell. Pre‐vascularized skeletal muscle‐like filaments are bioprinted by loading murine myoblasts (C2C12 cells) in gelatin methacryloyl ‐ alginate hydrogels and using hydroxyethyl cellulose as a sacrificial material. Higher viability and metabolic activity are observed in filaments with hollow multi‐channels than in solid constructs. The presence of hollow channels promotes the expression of Ki67 (a proliferation biomarker), mitigates the expression of hypoxia‐inducible factor 1‐alpha , and markedly enhances cell alignment (i.e., 82% of muscle myofibrils aligned (in ±10°) to the main direction of the microchannels after seven days of culture). The emergence of sarcomeric α ‐actin is verified through immunofluorescence and gene expression. Overall, this work presents an effective and practical tool for the fabrication of pre‐vascularized engineered tissues.
Combined over-the-scope clip and detachable snare placement as a rescue therapy for gastric ulcer rebleeding
Authors: Renato Medas, Eduardo Rodrigues-Pinto, Guilherme Macedo
Journal: Endoscopy (2022)

An 85-year-old woman, who had been admitted to an intermediate care unit of a peripheral hospital with relapsing ulcer bleeding, was referred to our department for upper gastrointestinal (GI) endoscopy for management of rebleeding. She had a history of hypertension and hypothyroidism, but was not taking antiplatelet or anticoagulant therapy. Two previous upper GI endoscopies had shown a Forrest IIa ulcer in the posterior wall of the proximal gastric body, which has been treated with adrenaline and through-the-scope (TTS) clips. The last endoscopic therapy had been performed 1 week previously.
Trans sigmoid colon NOTES sclerotherapy for polycystic liver disease
Authors: Tianyu Liu, Suyu He, Linlin Chen, Kai Jiang, Xiaomei Ding, Xiquan Wang, Ying Bi
Journal: Endoscopy (2022)

Laparoscopic cystic fluid aspiration is one of the common treatments for polycystic liver disease (PLD) [1]. However, laparoscopes have limited flexibility, and parts of the abdominal cavity are difficult to reach [2]. To avoid the problem of laparoscope inflexibility, we use the more flexible endoscope to perform sclerotherapy for polycystic liver disease by means of natural orifice transluminal endoscopic surgery (NOTES).
Immunity: Hypersensitivity, Serology
Journal: JAMA (1953)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
School screening for scoliosis.
Authors: D C Newman, R L DeWald
Journal: BMJ (1983)

During the past decade screening programmes for idiopathic scoliosis have been widely adopted in many countries.Recent evidence from Sweden and the United States suggests that early detection and treatment with a brace reduce the number of spinal fusions performed.1 2 In the United Kingdom screening programmes have been introduced in several areas and are under consideration by orthopaedic surgeons and community physicians in other centres.In September 1982 the council of the British Orthopaedic Association discussed the question of whether to screen for scoliosis.The council asked the British Scoliosis Society to provide specialist advice on the status of school screening for scoliosis in the United Kingdom.The executive of the British Scoliosis Society created a committee on school screening in February 1983 to collect information on school screening from centres in the British Isles.The committee consists of scoliosis surgeons and specialists in other disciplines including com- munity medicine (child health), radiology, community health, epidemiology, and health economics and members of the scoliosis self help group.Letters were sent to centres in the United Kingdom requesting reports, or expressions of opinion, on screening for scoliosis.Replies were received from individuals in 20 centres.Published information for the United Kingdom was collated.3 8A sum- mary of the report of the prevalence and natural history com- mittee of the Scoliosis Research Society was available.9After a meeting of the committee on school screening on 5 April 1983 the evidence was discussed at the annual general meeting of the British Scoliosis Society.A report was forwarded to the council of the British Orthopaedic Association, which met on 20 April 1983. Comments in the report(1) Twenty five per cent or more of healthy children examined in a recent study had asymmetry of the torso on forward bending, which creates difficulties for screeners.1i'The forward bending test alone is too sensitive and creates an unacceptably high number of false positive results.(2) The best ages at which to screen have yet to be decided.(3) Whether it is worth screening adolescent boys (who have established idiopathic scoliosis less frequently than girls) has to be determined.(4) The proportion of children referred to hospital after school
Endoscopic treatment of Bouveret syndrome with Holmium laser lithotripsy
Authors: Bülent Ödemiş, Çağdaş Erdoğan, Batuhan Başpınar, Orhan Coşkun, Mesut Zeki Yalın Kılıç
Journal: Endoscopy (2022)

Gallstone ileus is a rare condition that is seen in about 0.5 % of all cases of mechanical intestinal obstruction [1]. Furthermore, only 1 %–3 % of these patients have Bouveret syndrome, which is defined as the impaction of a large gallstone within the duodenum as a result of a cholecystoduodenal fistula [2]. Endoscopic baskets, mechanical lithotripsy, electrohydraulic lithotripsy, laser lithotripsy, and extracorporeal shockwave lithotripsy are the endoscopic treatment modalities used in Bouveret syndrome [3].
Tunneling and clip-with-line techniques for successful long circumferential esophageal endoscopic submucosal dissection
Authors: Daniela Falcão, Joana Alves-Silva, Sara Archer, Isabel Pedroto, Ricardo Marcos-Pinto, Ricardo Küttner-Magalhães
Journal: Endoscopy (2022)

A 67-year-old man with multiple comorbidities was referred to our institution owing to a recent diagnosis of a superficial esophageal squamous cell carcinoma. Endoscopic evaluation using white-light, narrow-band imaging and lugol chromoendoscopy revealed a circumferential 6-cm, Paris 0-IIa, type V3 intrapapillary capillary loop classification lesion, from 37 to 43 cm from the incisors. Multiple minor Paris 0-IIb + 0-IIc lesions were also observed proximally, up to 30 cm from the incisors. Following multidisciplinary evaluation, circumferential endoscopic submucosal dissection (ESD) was scheduled ([Video 1]). Proximal and distal circumferential incisions were made using a 1.5-mm DualKnife (Olympus, Tokyo, Japan). Next, two contralateral submucosal tunnels were accomplished, leaving two longitudinal lateral bridges. Then, the additional use of the clip-with-line technique allowed constant traction of the specimen, enabling dissection of the remaining lateral bridges. A full circumferential specimen 15 cm in length was retrieved. Lastly, triamcinolone acetonide was injected into the residual submucosal layer. The patient was discharged under oral prednisolone. Histological examination revealed an R0 resection of a 57–mm, well-differentiated squamous cell carcinoma, with lymphovascular invasion and submucosal invasion > 200 μm, along with additional R0, m3 squamous cell carcinoma and high-grade dysplastic lesions corresponding to the proximal lesions.
Management of intraoperative giant perforation of colorectal endoscopic submucosal dissection
Authors: Daisuke Ohki, Yosuke Tsuji, Rina Cho, Miho Obata, Hiroya Mizutani, Yoshiki Sakaguchi, Mitsuhiro Fujishiro
Journal: Endoscopy (2022)

Colorectal endoscopic submucosal dissection (ESD) is becoming the standard of care for colorectal tumors; however, troubleshooting for complications remains a challenge, particularly when dealing with large intraoperative perforations [1] [2] [3]. Here, we present a case where such a large perforation was successfully treated with polyglycolic acid (PGA) sheets and a purse-string suture method using a detachable snare.
A rare complication and proper management in cholangioenteric Roux-en-Y anastomosis
Authors: Junjing Zhang, Junjie Lu, Ang Li, Huijun Wang, Weihua Zheng
Journal: Endoscopy (2022)

Cholangioenteric Roux-en-Y anastomosis is a classic surgical approach for bile duct reconstruction. The common postoperative complications include anastomotic leakage and stenosis, cholangitis, and recurrent stone formation [1]. However, the occlusion of the manually created side-to-side anastomosis between the proximal jejunum and the jejunum at a distance of 40 cm from the cholangioenteric anastomosis is rare [2].